CN1280567A - Nitrogen-containing tetracyclic compounds - Google Patents
Nitrogen-containing tetracyclic compounds Download PDFInfo
- Publication number
- CN1280567A CN1280567A CN98811795.9A CN98811795A CN1280567A CN 1280567 A CN1280567 A CN 1280567A CN 98811795 A CN98811795 A CN 98811795A CN 1280567 A CN1280567 A CN 1280567A
- Authority
- CN
- China
- Prior art keywords
- acid
- alkyl
- compound
- ethyl
- hex
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 40
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract 1
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- -1 sec.-propyl Chemical group 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000001035 drying Methods 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 150000002475 indoles Chemical class 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 230000004799 sedative–hypnotic effect Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- VGUWZCUCNQXGBU-UHFFFAOYSA-N 3-[(4-methylpiperazin-1-yl)methyl]-5-nitro-1h-indole Chemical compound C1CN(C)CCN1CC1=CNC2=CC=C([N+]([O-])=O)C=C12 VGUWZCUCNQXGBU-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108010062745 Chloride Channels Proteins 0.000 description 3
- 102000011045 Chloride Channels Human genes 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229940049706 benzodiazepine Drugs 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000013016 damping Methods 0.000 description 3
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229910052738 indium Inorganic materials 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 150000004797 ketoamides Chemical class 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 3
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- 208000020358 Learning disease Diseases 0.000 description 2
- 208000000501 Lipidoses Diseases 0.000 description 2
- 206010024585 Lipidosis Diseases 0.000 description 2
- 208000002740 Muscle Rigidity Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- OEONOWYHIMSJQC-UHFFFAOYSA-N O=C1CC(OC2=CC=CC=C12)(C(=O)O)S(=O)(=O)O Chemical compound O=C1CC(OC2=CC=CC=C12)(C(=O)O)S(=O)(=O)O OEONOWYHIMSJQC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 206010013663 drug dependence Diseases 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 201000003723 learning disability Diseases 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 2
- 229940067157 phenylhydrazine Drugs 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KIGXMYYGQYMICF-UHFFFAOYSA-N Diphenylphosphine Acid Chemical compound C=1C=CC=CC=1P(=O)(CCCCC(=O)O)C1=CC=CC=C1 KIGXMYYGQYMICF-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 102000027484 GABAA receptors Human genes 0.000 description 1
- 108091008681 GABAA receptors Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010029897 Obsessive thoughts Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 108010061433 diazepam-binding inhibitor receptor Proteins 0.000 description 1
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000006229 isopropoxyethyl group Chemical group [H]C([H])([H])C([H])(OC([H])([H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- WSTNFGAKGUERTC-UHFFFAOYSA-N n-ethylhexan-1-amine Chemical compound CCCCCCNCC WSTNFGAKGUERTC-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006233 propoxy propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 230000003236 psychic effect Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical group 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 description 1
- 230000002557 soporific effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Nitrogen-containing tetracyclic compounds represented by general formula (I) or pharmaceutically acceptable salts thereof, wherein Y<1>-Y<2>-Y<3> represents N-C=N or C=C-NR<3> (wherein R<3> represents hydrogen, C1-5 alkyl or nitrogen-containing C2-10 alkyl); Y<4> represents S, SO, SO2, CH2 or NR<4> (wherein R<4> represents C1-5 alkanoyl or C1-5 alkyl); R<1> and R<2> are the same or different and each represents hydrogen, C1-10 alkyl, C3-15 alkoxyalkyl or C3-15 alkylaminoalkyl, or R<1> and R<2> form together with the adjacent nitrogen atom cyclic amino; X<1> and X<2> are the same or different and each represents hydrogen, C1-5 alkyl, C1-5 alkoxy or halogeno; and n is 0, 1 or 2.
Description
Technical field
The present invention relates to that plastosome diazepam binding inhibitors acceptor (mitochondrialdiazepam binding inhibitor receptor is called for short MDR) is had the compound than high-affinity.
Background technology
One of the site of action of sedative hypnotic Benzodiazepine (BZ) acceptor can be divided into center benzodiazepine _ acceptor (the centralbenzodiazepine receptor that is present on GABAA acceptor/chloride channel complex body, be called for short CBR) and be present in 2 kinds of (Clin.Neuropharmacol. of MDR on central nervous system (neurogliocyte) or the suprarenal gland, 16,401-417,1993).The CBR agonist of stable representative is widely used as sedative hypnotic, but because the CBR agonist directly acts on GABAA acceptor/chloride channel complex body, when showing sedative-hypnotic effect, also show side effects such as excessive calmness or psychic dependence.On the other hand, the MDR agonist is because by endogenous neuroactive steroids (endogenous tranquilizing soporific material)--synthesizing of neural cholesterol, indirect action is in GABAA acceptor/chloride channel, when showing sedative-hypnotic effect, also show side effect (J.Pharmacol.Exp.Ther. such as over-drastic calmness or neural dependency, 267,462-47l, 1993; Ibid., 265,649-656,1993).
Therefore, a kind of MDR agonist of expectation exploitation, as the curative of the curative effect of symptom (obsession, Phobias) can not give full play to to(for) former BZ class, and the sedative hypnotic that has alleviated the side effect of former BZ class.
In addition, to the compound of MDR effect because by the GABAA receptor acting, might become curative (the Progress inNeurobiology of insomnia obstacle, epilepsy, dyskinesia, the disturbance of food intake, cycle penalty, understanding learning disorder, drug dependence with muscular rigidity, 38,379-395,1992; Ibid, 49,73-97,1996, J.Neurochem.58,1589-1601; Neuropharmacol.30,1435-1440,1991).And, physiological function from MDR, might become cancer (Biochimica et BIOphysica Acta, 1241,453-470,1995), lipidosis (Eur.J.Pharmacol., 294,601-607,1995), schizophrenia (Neuropharmacology, 35,1075-1079,1996), cerebral infarction (J.Neurosci., 15,5263-5274,1995), ADIS (Abstracts of thefifth international conference on AIDS, P458,1989), Alzheimer's (Alzheimer Dis.Assoc.Disotd.2,331-336,1988) or prosperous front yard Dun Shi tarantism (Brain Res., 248,396-401,1982) curative.
As the compound that MDR is had affinity, have the spy and show disclosed Benzazole compounds in flat 6-501030 number.
The description of invention
The inventor found that specific nitrogenous tetracyclic compound has reached this purpose, thereby has finished the present invention for having the compound than high-affinity to carry out concentrated research with MDR.Known as mentioned above Benzazole compounds is the compound that MDR is had affinity, but report does not point out that nitrogenous tetracyclic compound has affinity to MDR.
That is to say that the present invention is nitrogenous tetracyclic compound or its pharmacologically acceptable salt of formula (I) expression.
(in the formula, Y
1-Y
2-Y
3Expression N-C=N or formula C=C-NR
3(R in the formula
3Expression hydrogen atom, C
1-5Alkyl or C
2-10Contain azanyl) shown in group.Y
4Expression S, SO, SO
2, CH
2Or NR
4(R in the formula
4Expression C
1-5Alkyloyl or C
1-5Alkyl) shown in group.R
1And R
2Identical or different, expression hydrogen atom, C
1-10Alkyl, C
3-15Alkoxyalkyl or C
3-15The alkylamino alkyl, perhaps R
1And R
2Together form cyclic amino with adjacent nitrogen-atoms.X
1And X
2Identical or different, expression hydrogen atom, C
1-5Alkyl, C
1-5The alkoxy or halogen atom, n represents 0,1 or 2)
In the present invention, R
3, R
4, X
1, X
2C
1-5Alkyl is represented straight chain shape, chain or cyclic alkyl, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, cyclopropyl methyl, amyl group, isopentyl etc.R
3C
2-10Contain azanyl for example methylamino-propyl group, dimethylaminoethyl, pyrrolidyl ethyl, 4-methylpiperazine base ethyl etc.R
4C
1-5Alkyloyl is formyl radical, ethanoyl, propionyl etc. for example.R
1, R
2C
1-10Alkyl is represented straight chain shape, chain or cyclic alkyl, for example methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, butyl, isobutyl-, cyclobutyl, cyclopropyl methyl, amyl group, isopentyl, cyclopentyl, cyclobutylmethyl, 1-ethyl propyl, hexyl, isohexyl, cyclohexyl, cyclopentyl-methyl, 1-ethyl-butyl, heptyl, different heptyl, cyclohexyl methyl, octyl group, nonyl, decyl etc.R
1, R
2C
3-5Alkoxyalkyl is represented straight chain shape, chain or cyclic C
1-13Alkoxy-C
2-14Alkyl, for example methoxy ethyl, methoxy-propyl, methoxyl group butyl, ethoxyethyl group, ethoxycarbonyl propyl, oxyethyl group butyl, oxyethyl group amyl group, oxyethyl group hexyl, oxyethyl group heptyl, propoxy-ethyl, propoxy-propyl group, propoxy-butyl, isopropoxy ethyl, cyclo propyl methoxy ethyl etc.R
1, R
2C
3-15The alkylamino alkyl is represented straight chain shape, chain or cyclic C
1-13Alkylamino-C
2-14Alkyl, for example methylamino-ethyl, dimethylaminoethyl, methylamino-propyl group, dimethylamino-propyl, methylamino-butyl, ethylamino ethyl, ethylamino propyl group, ethylamino butyl, ethylamino amyl group, ethylamino hexyl, ethylamino heptyl, ethylamino octyl group, third amino-ethyl, third aminopropyl, the third amino butyl, isopropylamino ethyl, cyclopropyl methylamino-ethyl, pyrrolidyl ethyl etc.R
1, R
2And the cyclic amino that forms of the nitrogen-atoms that is adjacent for example pyrrolidyl, piperidyl, homopiperidinyl, morpholinyl, piperazinyl, N methyl piperazine base, 3,5-lupetazin base etc.X
1, X
2C
1-5Alkoxyl group is represented straight chain shape, chain or cyclic alkoxy, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, cyclo propyl methoxy, pentyloxy, isopentyloxy etc.X
1, X
2Halogen atom represent fluorine atom, chlorine atom, bromine atoms or iodine atom.
In addition, the pharmacologically acceptable salt among the present invention is the salt that forms with mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, with the salt of organic acids formation such as acetic acid, oxalic acid, lactic acid, tartrate, fumaric acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid.
The compound of formula (I) can adopt following conventional preparation method 1～6 preparation (in the following reaction formula, Y
1, Y
2, Y
3, Y
4, R
1, R
2, X
1, X
2Same as described above with n, R
5Expression hydrogen atom or C
1-5Alkyl, R
6Expression C
1-5Alkyl or C
2-10Contain azanyl, R
7And R
8Identical or different, expression C
1-5Alkyl or phenmethyl, X
3Expression chlorine atom, bromine atoms or iodine atom, X
4Expression fluorine atom, chlorine atom, bromine atoms or iodine atom, Boc represents tert-butoxycarbonyl).(conventional preparation method 1)
Steps A: use ketoacid derivatives (1) and phenylhydrazine derivant (2), adopt the Fei Xier indole synthesis to make tetracyclic indole derivatives (3).The R of tetracyclic indole derivatives (3)
5Be C
1-5During alkyl, its ester can derive carboxylic acid derivative (R by common alkali or acid hydrolysis
5=H).
Step B: via carboxylic acid halides or mixed acid anhydride etc., can synthesize compound of the present invention (5) by tetracyclic indole derivatives (3).
Here carboxylic acid halides is represented acyl chlorides, acylbromide etc., can pass through thionyl chloride, thionyl bromide, oxalyl chloride, tetracol phenixin-triphenyl phosphatization hydrogen, carbon tetrabromide-halogenating agents such as triphenyl phosphatization hydrogen in inert solvent with tetracyclic indole derivatives (3) (R
5=H) reaction makes.Described inert solvent is ethers such as tetrahydrofuran (THF); Hydro carbons such as toluene, benzene; Halogenated hydrocarbon solvent such as chloroform, methylene dichloride, acetonitrile, N, dinethylformamide etc.
Mixed acid anhydride is represented carboxylic acid derivative (3) (R
5=the acid anhydrides that H) forms with carbonic ether or carboxylic acid etc., can pass through halo carbonic ethers such as chlorine ethyl-carbonate, chlorine isobutyl carbonate butyl ester, or carboxylic-acid such as acetic acid, propionic acid, phenylformic acid, naphthoic acid, in the presence of mineral alkalis such as organic basess such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or sodium hydroxide, in inert solvent, react and make.Described inert solvent is ethers such as tetrahydrofuran (THF); Hydro carbons such as toluene, benzene; Halogenated hydrocarbon solvent such as chloroform, methylene dichloride, acetonitrile, N, dinethylformamide etc.
In addition, The compounds of this invention (5) also can make by tetracyclic indole derivatives (3) is reacted in inert solvent with condensing agent and amine (4).
The condensing agent is here represented normally used amidation reagent, for example diphenylphosphine acid amides, diethyl phosphorocyanidate, carbonyl dimidazoles, N, N ' dicyclohexyl carbodiimide, N-ethyl-N '-dimethylamino-propyl carbodiimide hydrochloride etc.Inert solvent for example 1, ethers such as 2-glycol dimethyl ether, tetrahydrofuran (THF); Hydro carbons such as toluene, benzene; Halogenated hydrocarbon solvent such as chloroform, methylene dichloride; Acetonitrile, N, dinethylformamide etc.In addition, originally be reflected at and can add N-hydroxy-succinamide, I-hydroxybenzotriazole or 3-hydroxyl-4-oxo-3 in case of necessity, 4-dihydro-1,2,3-phentriazines etc. are as activator.(conventional preparation method 2)
After The compounds of this invention (5) also can carry out the amidation of step B by ketone acid (6), the keto-amide derivative (7) that obtains is reacted under the Fei Xier of steps A indoles synthesis condition make.(conventional preparation method 3)
Step C: by making tetracyclic compound (5) and halogenated compound (8) in inert solvent, alternate moving catalyst existence is arranged or do not have alternate moving catalyst to exist down, reacting with alkali one to make The compounds of this invention (9).
The inert solvent here is alcohols such as methyl alcohol, ethanol for example; 1, ethers such as 2-glycol dimethyl ether, tetrahydrofuran (THF); Hydro carbons such as toluene, benzene; Halogenated hydrocarbon solvent such as chloroform, methylene dichloride; Acetonitrile, N, dinethylformamide etc.Alternate moving catalyst is quaternary ammonium salt such as phenmethyl triethyl ammonium bromide, TBuA bromide for example; Crown ethers such as 18-hat-6-ether etc.Alkali is inorganic bases such as salt of wormwood, sodium hydroxide, sodium hydride, sodium Metal 99.5 for example; Alcoholate such as potassium tert.-butoxide, sodium ethylate etc.(conventional preparation method 4)
Step D: by making 2-cyano group phenmethyl halogenide (10) and 2-amidomalonic acid diester deriv (11) in inert solvent, alternate moving catalyst existence is arranged or do not have alternate moving catalyst to exist down, reacting with alkali one to make phenmethyl malonate derivative (12).
Here inert solvent alcohols such as methyl alcohol, ethanol for example; 1, ethers such as 2-glycol dimethyl ether, tetrahydrofuran (THF); Hydro carbons such as toluene, benzene; Halogenated hydrocarbon solvent such as chloroform, methylene dichloride; Acetonitrile, N, dinethylformamide etc.Alternate moving catalyst is quaternary ammonium salt such as phenmethyl triethyl ammonium bromide, TBuA bromide for example; Crown ethers such as 18-hat-6-ether etc.Alkali is mineral alkalis such as salt of wormwood, sodium hydroxide, sodium hydride, sodium Metal 99.5 for example; Alcoholate such as potassium tert.-butoxide, sodium ethylate etc.
Step e: phenmethyl malonate derivative (12) is in inert solvent, and by alkali or sour with the ester hydrolysis, decarboxylation can obtain Phenylalamine derivatives (13) then.Here inert solvent alcohols such as methyl alcohol, ethanol for example; 1, ethers such as 2-glycol dimethyl ether, tetrahydrofuran (THF); Hydro carbons such as toluene, benzene; Halogenated hydrocarbon solvent such as chloroform, methylene dichloride; Acetonitrile, N, dinethylformamide, water or its mixed solvent.Alkali is mineral alkalis such as salt of wormwood, yellow soda ash, potassium hydroxide, sodium hydroxide for example, and acid is hydrochloric acid, sulfuric acid, phosphoric acid etc. for example.
And Phenylalamine derivatives (13) is by after the step B reaction, and with mineral acid treatment deprotections such as organic acid such as trifluoracetic acid, formic acid or hydrogenchloride, hydrochloric acid, Hydrogen bromide, sulfuric acid, can derive obtains amide compound (14).
Step F: amide compound (14) is having in the presence of the alkali or is not having in the presence of the alkali, with nitrobenzene derivative (15) reaction, can derive anils (16) in inert solvent.
Here alkali mineral alkalis such as salt of wormwood, yellow soda ash, sodium hydroxide, sodium hydride, sodium Metal 99.5 for example, alcoholate such as potassium tert.-butoxide, sodium ethylate, organic basess such as triethylamine, diisopropylethylamine, pyridine etc.Inert solvent is alcohols such as methyl alcohol, ethanol for example; 1, ethers such as 2-glycol dimethyl ether, tetrahydrofuran (THF); Hydro carbons such as toluene, benzene; Halogenated hydrocarbon solvent such as chloroform, methylene dichloride; Acetonitrile, N, dinethylformamide etc.
Step G: after the nitro of anils (16) reduces,, can make The compounds of this invention (17) in inert solvent by in inert solvent, carrying out acid treatment.
Here reduction is meant the hydrogenation that uses platinum dioxide, palladium etc., or uses the metallic reducing of metal-salts such as metal such as tin, iron, zinc or tin protochloride under acid, neutrality or alkaline condition.At this moment inert solvent is alcohols such as methyl alcohol, ethanol for example; Ethers such as Anaesthetie Ether, tetrahydrofuran (THF); Hydro carbons such as toluene, benzene; Halogenated hydrocarbon solvent such as methylene dichloride, chloroform; Acetonitrile, N, organic carboxyl acids such as dinethylformamide, acetic acid, water or its mixed solvent etc.Acid treatment in the inert solvent is in the independent solvent of alcohols such as methyl alcohol, ethanol, or at halogenated hydrocarbon solvent, N such as hydro carbons such as ethers such as Anaesthetie Ether, tetrahydrofuran (THF), toluene, benzene, methylene dichloride, chloroforms, in the mixed solvent of dinethylformamide etc. and alcohol, use acid such as hydrogenchloride, hydrogen bromide, sulfuric acid, trifluoracetic acid to react.(conventional preparation method 5)
Step H: can obtain racemization or optically active sulfoxide derivant (19) or sulfone derivatives (20) by the tetracyclic compound (18) that in inert solvent, contains sulphur atom with oxidizer treatment.
Here inert solvent alcohols such as methyl alcohol, ethanol for example; Ethers such as Anaesthetie Ether, tetrahydrofuran (THF); Hydro carbons such as toluene, benzene; Halogenated hydrocarbon solvent such as methylene dichloride, chloroform; Acetonitrile, N, organic carboxyl acids such as dinethylformamide, acetic acid, water or its mixed solvent etc.Oxygenant is percarboxylic acids such as metachloroperbenzoic acid, peroxyacetic acid for example, or hydrogen peroxide, Potassium peroxide (OXONE, 2KSO
5KHSO
4K
2SO
4) wait inorganic peroxide.
Step I: the HPLC that optically active body (22) also can be by using chiral stationary phase splits the raceme (21) of The compounds of this invention and makes.
Here chiral stationary phase is derivatives such as cellulose ester, cellulose carbamate, amylose starch carbamate, crown ether, polymethacrylate.
Step J: form salt by carboxylic acid derivative (23) with Chiral Amine, can split into optically active body (24) with raceme.
Here Chiral Amine is (+) or (-)-1-phenyl-ethyl amine, (+) or (-)-2-amino-1-butanols, (+) or (-)-aminopropanol (ア ラ ニ ノ-Le), vauqueline, Cinchonidune, cinchonine, quinine, Quinidine, dehydroabietylamine etc.
Optically active body (22) can obtain optically active body (24) amidation by step B.(conventional preparation method 7)
R is worked as in The compounds of this invention (21) or (22) shown in the conventional preparation method 6
1, R
2In one of or both when all containing by the nitrogen-atoms of protection such as acyl group, alkoxy carbonyl, can slough these protecting groups by acid or alkali, obtain compound of the present invention.
Here acid expression trifluoracetic acid, formic acid, hydrogenchloride, hydrogen bromide, hydrochloric acid, Hydrogen bromide etc., alkali is represented salt of wormwood, yellow soda ash, potassium hydroxide, sodium hydroxide, lithium hydroxide, hydrated barta etc.Industrial applicibility
Compound of the present invention has higher affinity to MDR.Therefore, be effective as central diseases such as the disease of uneasy or associated company, depressive illness, epilepsy, somnopathy, understanding learning disorder, schizophrenia, dyskinesia, the disturbance of food intake, cycle penalty, drug dependence, cancer, lipidosis, cerebral infarction, AIDS, Alzheimer's or the choreic treatment of prosperous front yard Dun Shi or prophylactic agent with muscular rigidity.
The preferred forms of invention
Specify the present invention below in conjunction with embodiment and experimental example.
Embodiment 1
N-2-(propyl group amino) ethyl-N-hexyl-6, the preparation of 11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide
(1) in the ethanol 1OOml solution of (4-oxo-sulfo-chroman-2-yl)-formic acid 22.54g and phenylhydrazine 10.7ml, adds sulfuric acid 15ml, reflux 5 hours.With the reaction solution cool to room temperature, be injected among the frozen water 500ml, use extracted with diethyl ether.With saturated common salt water washing extraction liquid, behind anhydrous sodium sulfate drying, remove by filter siccative, concentrated filtrate under reduced pressure, residue with ethanol-hexane recrystallization, is obtained 6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-ethyl formate 21.85g.
(2) potassium hydroxide 19.46g is dissolved among the water 40ml, joins 6, in the ethanol 100ml solution of 11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-ethyl formate 21.63g.After the reflux 2 hours, in reaction soln, drip concentrated hydrochloric acid, be adjusted to pH=3, use ethyl acetate extraction.With saturated common salt water washing extraction liquid, behind anhydrous sodium sulfate drying, remove by filter siccative, concentrated filtrate under reduced pressure with ethanol-hexane recrystallization, obtains 6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-formic acid 19.94g with residue.
m．p．141．5～142．5℃
(3) 6, add I-hydroxybenzotriazole monohydrate 552mg and N-ethyl-N '-dimethylamino-propyl carbodiimide hydrochloride 863mg in the methylene dichloride 44ml solution of 11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-carboxylic acid 844mg and N-2-(N-tert-butoxycarbonyl propyl group amino) ethyl-hexylamine 1.66g, at room temperature stirred for 1 night.Under the reduced pressure behind the concentration of reaction solution, be dissolved in ethyl acetate, water, the 5% sodium pyrosulfate aqueous solution, saturated sodium bicarbonate aqueous solution, the saturated common salt water washing, behind anhydrous sodium sulfate drying, remove by filter siccative, concentrated filtrate under the reduced pressure, with flash chromatography (silica gel: Chromatrex NHDM 1020 (production of Devisone chemical company of Fuji), launch solvent: hexane-ethyl acetate=2: 1～3: 2) handle residue, obtain unbodied N-2-(N-tert-butoxycarbonyl propyl group amino) ethyl-N-hexyl-6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide 1.35g.
(4) in 99% formic acid 4.2ml, with N-2-(N-tert-butoxycarbonyl propyl group amino) ethyl-N-hexyl-6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide 600mg stirred 5 hours.Under the reduced pressure behind the concentration of reaction solution, be dissolved in ethyl acetate, with saturated sodium bicarbonate aqueous solution, saturated common salt water washing, behind anhydrous sodium sulfate drying, remove by filter siccative, concentrated filtrate under reduced pressure is with the residue re-crystallizing in ethyl acetate, obtain N-2-(propyl group amino) ethyl-N-hexyl-6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide 406mg.
The structure and the physical data of the compound that this compound and employing same procedure obtain are as shown in table 1.
Embodiment 2
N, N-dihexyl-6, the preparation of 11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide
(1) in the benzene 200ml solution of (4-oxo-sulfo-chroman-2-yl)-formic acid 20.00g, adds thionyl chloride 14.0ml, reflux 3 hours.Concentration of reaction solution under the reduced pressure under the ice-water bath condition, is added drop-wise to the methylene dichloride 100ml solution of this residue in the methylene dichloride 200ml solution of dihexyl amine 24.6ml and triethylamine 20.0ml while stirring.After at room temperature stirring for 1 night, the concentrating under reduced pressure reaction solution adds ethyl acetate in residue, and water, 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing behind anhydrous sodium sulfate drying, remove by filter siccative, concentrating under reduced pressure filtrate.Adopt chromatography (silica gel: WacogelC 200 (with the pure medicine production of light), launch solvent: after hexane-ethyl acetate=5: 1～3: 1) making with extra care residue, use the hexane recrystallization, obtain N, N-dihexyl-(4-oxo-sulfo-chroman-2-yl)-methane amide 29.22g.
(2) with N, N-dihexyl-(4-oxo-sulfo-chroman-2-yl)-methane amide l.00g with phenylhydrazine 0.26ml 100 ℃ down stir 30 minutes after, under 50 ℃ of conditions of decompression with dry 30 minutes of reaction mixture.In residue, add Zinc Chloride Anhydrous 1.44g, stirred cool to room temperature 5 minutes down at 170 ℃.In reaction mixture, add frozen water, use ethyl acetate extraction,, behind anhydrous sodium sulfate drying, remove by filter siccative, concentrating under reduced pressure filtrate with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing.Residue with ethyl acetate-hexane recrystallization, is obtained N, N-dihexyl-6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide 0.79g.
(3) with the N of raceme, N-dihexyl-6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide high performance liquid chromatography (chiralpak AD (production of Daicel company), 2 φ * 25cm, mobile phase: hexane-ethanol=3: 7, flow velocity: 5ml/min) split.
(-)-N, N-dihexyl-6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide [α]
D 26-25.9 (c=0.180, EtOH), retention time: 20min.
(+)-N, N-dihexyl-6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide [α]
D 26+ 25.9 (c=O.207, EtOH), retention time: 37min.
The structure of the compound that this compound and employing same procedure obtain and physical data are shown in table 1,2.
Embodiment 3
N, N-dihexyl-6, the preparation of 11-dihydro-11-methyl-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide
At N, N-dihexyl-6, the N of 11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide 200mg adds 60% sodium hydride/oily 21mg in the dinethylformamide 1Oml solution, at room temperature stirred 1 hour.In this solution, add methyl iodide 33 μ l, at room temperature stirred 5 hours.Add ethyl acetate in reaction soln, water, 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing behind anhydrous sodium sulfate drying, remove by filter siccative, concentrating under reduced pressure filtrate.With residue hexane recrystallization, obtain N, N-dihexyl-6,11-dihydro-11-methyl-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide 155mg.
The structure and the physical data of the compound that this compound and employing same procedure obtain are as shown in table 2.
Embodiment 4
N, N-dihexyl-5,6-dihydro-benzo (4,5) imidazo (2,1-a) isoquinoline 99.9-6-methane amide
(1) sodium 0.49g is dissolved among the ethanol 20ml, at room temperature while stirring to the ethanol 10ml solution that wherein adds 2-N-tert-butoxycarbonyl amidomalonic acid diethyl ester 5.90g.Stir after 20 minutes, in reaction solution, add the ethanol 10ml solution of 2 one cyano group phenmethyl bromide 4.00g, at room temperature stirred 10 minutes, under reflux, stirred 3.5 hours again.The concentrating under reduced pressure reaction solution adds ethyl acetate in residue, water, 5% aqueous potassium hydrogen sulfate, saturated sodium bicarbonate aqueous solution, saturated common salt water washing behind anhydrous sodium sulfate drying, remove by filter siccative, concentrating under reduced pressure filtrate.(silica gel: Wacogel C 200 (with the pure medicine production of light) launches solvent: hexane one ethyl acetate=5: 1) make with extra care residue, obtain buttery 2-(2-cyano group phenmethyl)-2-N-tert-butoxycarbonyl amidomalonic acid diethyl ester 7.86g to adopt chromatography.
(2) in 2-(2-cyano group phenmethyl)-2-N-tert-butoxycarbonyl amidomalonic acid diethyl ester 1.17g, add ethanol 20ml and aqueous sodium hydroxide solution (sodium hydroxide O.36g/ water O.5ml), under reflux, stirred 2 hours.The concentrating under reduced pressure reaction solution adds 5% aqueous potassium hydrogen sulfate in residue, use ethyl acetate extraction.With saturated common salt water washing extraction liquid, behind anhydrous sodium sulfate drying, remove by filter siccative, concentrating under reduced pressure filtrate obtains the thick N-tert-butoxycarbonyl of buttery-(2-cyano-phenyl) L-Ala 0.81g.This compound is not made with extra care and is directly used in next step.
(3) thick N-tert-butoxycarbonyl-(2-cyano-phenyl) L-Ala 0.81g and dihexyl amine 0.67g are dissolved in N, among the dinethylformamide 8ml, to wherein add I-hydroxybenzotriazole monohydrate 0.55g and N-ethyl-N-dimethylamino-propyl carbodiimide hydrochloride 0.69g, at room temperature stir for 1 night.Reaction mixture is injected in the water, uses ethyl acetate extraction,, behind anhydrous sodium sulfate drying, remove by filter siccative, concentrating under reduced pressure filtrate with 5% aqueous potassium hydrogen sulfate, saturated sodium bicarbonate aqueous solution, saturated common salt water washing.(silica gel: Wacogel C 200 (with the pure medicine production of light) launches solvent: hexane-ethyl acetate=4: 1) make with extra care residue, obtain N-tert-butoxycarbonyl-(2-cyano-phenyl) L-Ala dihexyl acid amides 1.01g with chromatography.
(4) O.98g N-tert-butoxycarbonyl-(2-cyano-phenyl) L-Ala dihexyl acid amides is dissolved among the methylene dichloride 1.7ml, adds trifluoracetic acid 1.7ml, at room temperature stirred 1.5 hours.The concentrating under reduced pressure reaction solution adds saturated sodium bicarbonate aqueous solution in residue, use dichloromethane extraction, use the saturated common salt water washing, behind anhydrous sodium sulfate drying, remove by filter siccative, concentrating under reduced pressure filtrate obtains thick (2-cyano-phenyl) L-Ala dihexyl acid amides 0.76g.This compound is not made with extra care and is directly used in next step.
(5) slightly (2-cyano-phenyl) L-Ala dihexyl acid amides 0.76g, 2-fluoronitrobenzene 0.30g and Anhydrous potassium carbonate 0.36g are at N, and reflux is 2.5 hours among the dinethylformamide 8ml.Reaction mixture is injected water, use ethyl acetate extraction, water, saturated common salt water washing behind anhydrous sodium sulfate drying, remove by filter siccative, concentrating under reduced pressure filtrate.(silica gel: Wacogel C 200 (with the pure medicine production of light) launches solvent: hexane-ethyl acetate=5: 1) make with extra care residue, obtain N-(2-nitrophenyl)-(2-cyano-phenyl) L-Ala dihexyl acid amides 0.42g to adopt chromatography.
(6) with N-(2-nitrophenyl)-(2-cyano-phenyl) L-Ala dihexyl acid amides 95mg and platinum dioxide 10mg in methyl alcohol 3ml, hydrogen environment stirred 2 hours down.After using the diatomite plate to remove by filter insolubles, concentrating under reduced pressure filtrate.
Residue is dissolved among the ethanol 5ml,, obtains saturated solution to wherein feeding hydrogen chloride gas.The reaction solution stirring after 4 hours, is injected in the saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction.With saturated common salt water washing extraction liquid, behind anhydrous sodium sulfate drying, remove by filter siccative, concentrating under reduced pressure filtrate.(silica gel: Wacogel C 200 (with the pure medicine production of light) launches solvent: after hexane-ethyl acetate=2: 1) making with extra care residue, use re-crystallizing in ethyl acetate to adopt chromatography, obtain N, N-dihexyl-5,6-dihydro-benzo (4,5) imidazo (2,1-a) isoquinoline 99.9-6-methane amide 24mg.
The structure and the physical data of the compound that this compound and employing same procedure obtain are as shown in table 3.
Embodiment 5
N, N-dipropyl-6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide 5, the preparation of 5-dioxide
Under the ice-water bath condition, with 20 minutes while stirring to N, N-dipropyl-6 drips the methylene dichloride 30ml solution of metachloroperbenzoic acid (containing more than 70%) 710mg in the methylene dichloride 30ml solution of 11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide 500mg.After at room temperature stirring 1 hour again, the concentrating under reduced pressure reaction mixture is dissolved in ethyl acetate with residue, with saturated sodium bicarbonate aqueous solution, saturated common salt water washing, behind anhydrous sodium sulfate drying, removes by filter siccative, concentrating under reduced pressure filtrate.Adopt chromatography (silica gel: Wacogel C 200 (with the pure medicine production of light), launch solvent: after hexane-ethyl acetate=3: 1～1: 1) making with extra care residue, with ethyl acetate-hexane recrystallization, obtain N, N-dipropyl-6,11-dihydro-5-sulfo--11-azepine-benzo (a) fluorenes-6-methane amide 5,5-dioxide 230mg.
The structure and the physical data of the compound that this compound and employing same procedure obtain are as shown in table 2.
Table 1
| Comp. No. *1 | Exp. No. *1 | ?R 1 | ????R 2 | n | ????X 1 | X 2 | ????R 3 | ????Y 4 | ????m.p.(Recry.sol. *1) ????(℃) |
| ?01 ?02 ?03 ?04 ?05 ?06 ?07 *4?08 *4?09 ?10 ?11 ?12 ?13 ?14 ?15 | ?2 ?2 ?2 ?2 ?2 ?2 ?2 ?2 ?2 ?2 ?2 ?2 ?1 ?1 ?2 | ?H ?n-Pr ?Me ?Et ?n-Pr ?n-Hex ?n-Hex ?n-Hex ?n-Hex ?n-Hex ?n-Hex ?n-Hex ?n-Hex ?n-Hex ?CH 2O(CH 2) 2 | ????H ????H ????Me ????Et ????n-Pr ????n-Hex ????n-Hex ????n-Hex ????n-Hex ????n-Hex ????n-Hex ????n-Hex CH 3(CH 2) 2NH(CH 2) 2CH 3(CH 2) 2O(CH 2) 2*CH 2O(CH 2) 2 | ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O ?O | ????H ????H ????H ????H ????H ????H ????H ????H ??8-F ??8-Cl ??8-Me ??8-F ??H ??H ??H | ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H ?H 10-F ?H ?H ?H | ????H ????H ????H ????H ????H ????H ????H ????H ????H ????H ????H ????H ????H ????H ????H | ????S ????S ????S ????S ????S ????S ????S ????S ????S ????S ????S ????S ????S ????S ????S | 241.0～242.5 (AcOE1) 172.0～174.0 (AcOEt/Hex) 254.5～256.5 (AcOEt) 242.0～243.5 (AcOEt) 196.0～197.0 (AcOEt) 138.5～140.0 (AcOEt/Hex) 99.0～100.5 (place*4) 98.0～99.0 (placements *4) 110.5～112.5(AcOEt/Hex) 123.0～124.5(AcOEt/Hex) 139.5～141.5(AcOEt/Hex) 148.0～149.0(AcOEt/Her) 135.5～138.0(AcOEt) 165.0～167.0(AcOEt) 206.0～208.0(AcOEt) |
* 1: compound number
* 2: the embodiment numbering that compound is synthetic used
* 3: recrystallization solvent AcOEt=ethyl acetate, Hex=hexane, Et
2The O=Anaesthetie Ether
* 4: the optically active body of compound 6 (compound 7=(-)-compound 6, compound 8=(+)-compound 6)
* 5: post is refining, after the drying, place and make it crystallization.
In addition, R
1, R
2In, n-Hex=n-hexyl, n-Pr=n-propyl.
Table 2
* 1: compound number
* 2: the embodiment numbering that compound is synthetic used
* 3: recrystallization solvent AcOEt=ethyl acetate, Hex=ethane, Et
2The O=Anaesthetie Ether
* 4:1 hydrochloride
In addition, R
1, R
2In, n-Hex=is base, n-Pr=n-propyl just.
Table 3
* 1: compound number
* 2: the embodiment numbering that compound is synthetic used
* 3: recrystallization solvent AcOEt=ethyl acetate, Hex=hexane
* 4: post is refining, after the drying, place, and carries out crystallization.
In addition, R
1, R
2In, n-Hex=n-hexyl, n-Pr=n-propyl.Test example (MDR receptor binding assays)
The thick line plastochondria part that use makes from rat cerebral cortex is as the acceptor standard substance.
Use [
3H] the PK11195 conduct [
3H] the sign part.
Use [
3H] the sign part in conjunction with test according to Journal of Pharmacologyand Experimental Therapeutics, the following method of 262,971 (1992) records is carried out.
The preparation of acceptor standard substance: use the tetrafluoroethylene homogenizer, with the 10mM Hepes damping fluid (pH7.4) of the 0.32M sucrose that contains 10 times of capacity of its wet weight, with the pallium homogenize.With 900 * g with homogenate centrifugation 10 minutes.With the supernatant liquor that obtains with 9000 * g centrifugation 10 minutes.Sediment is outstanding turbid in the Hepes damping fluid, make protein concn reach 1mg/ml, with 12000 * g centrifugation 10 minutes.The sediment that obtains is outstanding turbid in 50mM Hepes damping fluid (pH7.4), obtain thick line plastochondria part.
MDR is in conjunction with test: make the plastosome standard substance (1.0mg protein/ml), [
3H] PK11195 (2nM) and tested medicine be 4 ℃ of reactions 90 minutes down.
Reaction is used glass filter (GF/B) suction filtration of handling through 0.3% polymine after finishing, and decides the reflected energy of filter paper with the liquid scintillation instrumentation.
When having down reaction with 10 μ MPK11195 in conjunction with as [
3H] the non-specific combination of PK11195, with the difference of total binding and non-specific combination as specific combination.Certain density by making [
3H] the tested medicine that changes of PK11195 (2nM) and concentration reacts the curve that is inhibited under these conditions, by this inhibitions curve obtain 50% inhibition [
3H] the tested drug level (IC of PK11195 bonded
50), the result is as shown in table 4.Table 4
| Comp． No． | ????MDR ????IC 50(nM) |
| ????02 ????03 ????04 ????05 ????06 ????07 ????08 ????09 ????10 ????11 ????12 ????14 ????15 ????16 ????21 ????22 ????23 ????25 ????26 ????27 ????28 | ????55．9 ????38．5 ????0．443 ????0．368 ????3．76 ????42．3 ????2．15 ????13．8 ????20．1 ????13．9 ????22．1 ????1．35 ????4．98 ????1．35 ????1．12 ????1．23 ????1．35 ????73．9 ????42．3 ????35．1 ????12．6 |
Claims (1)
- The nitrogenous tetracyclic compound that l, following formula are represented or its pharmacologically acceptable salt.
In the formula, Y 1-Y 2-Y 3Expression N-C=N or formula C=C-NR 3(R in the formula 3Expression hydrogen atom, C 1-5Alkyl or C 2-10Contain azanyl) shown in group; Y 4Expression S, SO, SO 2, CH 2Or NR 4(R in the formula 4Expression C 1-5Alkyloyl or C 1-5Alkyl) shown in group; R 1And R 2Identical or different, expression hydrogen atom, C 1-10Alkyl, C 3-15Alkoxyalkyl or C 3-16The alkylamino alkyl, perhaps R 1And R 2Together form cyclic amino with adjacent nitrogen-atoms; X 1And X 2Identical or different, expression hydrogen atom, C 1-5Alkyl, C 1-5The alkoxy or halogen atom, n represents 0,1 or 2.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP332538/1997 | 1997-12-03 | ||
| JP33253897 | 1997-12-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1280567A true CN1280567A (en) | 2001-01-17 |
| CN1161334C CN1161334C (en) | 2004-08-11 |
Family
ID=18256047
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988117959A Expired - Fee Related CN1161334C (en) | 1997-12-03 | 1998-12-03 | Nitrogen-containing tetracyclic compounds |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US6281355B1 (en) |
| EP (1) | EP1048651B1 (en) |
| KR (1) | KR20010032668A (en) |
| CN (1) | CN1161334C (en) |
| AT (1) | ATE240295T1 (en) |
| AU (1) | AU736227B2 (en) |
| CA (1) | CA2313054A1 (en) |
| DE (1) | DE69814690T2 (en) |
| DK (1) | DK1048651T3 (en) |
| ES (1) | ES2198773T3 (en) |
| HK (1) | HK1034073A1 (en) |
| PT (1) | PT1048651E (en) |
| WO (1) | WO1999028298A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0523506D0 (en) * | 2005-11-18 | 2005-12-28 | Hammersmith Imanet Ltd | Novel in vivo imaging compounds |
| GB0818738D0 (en) * | 2008-10-13 | 2008-11-19 | Ge Healthcare Ltd | Imaging neuroflammation |
| GB0905328D0 (en) * | 2009-03-27 | 2009-05-13 | Ge Healthcare Ltd | Indole derivatives |
| US9220795B2 (en) | 2011-09-22 | 2015-12-29 | Ge Healthcare Limited | Indole derivatives |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1816984B2 (en) | 1968-12-24 | 1973-05-30 | Farbwerke Hoechst AG, vormals Meister Lucius & Brüning, 6000 Frankfurt | LOW-DUST, POWDER-FORMED COLORING PREPARATIONS FOR ICE PAINTING |
| US5206382A (en) | 1991-06-27 | 1993-04-27 | Fidia Georgetown Institute For The Neurosciences | Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders |
| US5750702A (en) * | 1993-10-27 | 1998-05-12 | Neurogen Corporation | Certain pyrrolo pyridine-3-carboxamides; a new class of GABA brain receptor ligands |
| US5792766A (en) * | 1996-03-13 | 1998-08-11 | Neurogen Corporation | Imidazo 1,5-c! quinazolines; a new class of GABA brain receptor ligands |
-
1998
- 1998-12-03 KR KR1020007005950A patent/KR20010032668A/en not_active Application Discontinuation
- 1998-12-03 CA CA002313054A patent/CA2313054A1/en not_active Abandoned
- 1998-12-03 AT AT98957146T patent/ATE240295T1/en not_active IP Right Cessation
- 1998-12-03 PT PT98957146T patent/PT1048651E/en unknown
- 1998-12-03 ES ES98957146T patent/ES2198773T3/en not_active Expired - Lifetime
- 1998-12-03 AU AU13510/99A patent/AU736227B2/en not_active Ceased
- 1998-12-03 DK DK98957146T patent/DK1048651T3/en active
- 1998-12-03 EP EP98957146A patent/EP1048651B1/en not_active Expired - Lifetime
- 1998-12-03 WO PCT/JP1998/005452 patent/WO1999028298A1/en not_active Application Discontinuation
- 1998-12-03 DE DE69814690T patent/DE69814690T2/en not_active Expired - Fee Related
- 1998-12-03 CN CNB988117959A patent/CN1161334C/en not_active Expired - Fee Related
- 1998-12-03 US US09/555,570 patent/US6281355B1/en not_active Expired - Fee Related
-
2001
- 2001-06-28 HK HK01104483A patent/HK1034073A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE240295T1 (en) | 2003-05-15 |
| US6281355B1 (en) | 2001-08-28 |
| AU736227B2 (en) | 2001-07-26 |
| AU1351099A (en) | 1999-06-16 |
| EP1048651A1 (en) | 2000-11-02 |
| EP1048651A4 (en) | 2001-09-19 |
| CA2313054A1 (en) | 1999-06-10 |
| ES2198773T3 (en) | 2004-02-01 |
| EP1048651B1 (en) | 2003-05-14 |
| WO1999028298A1 (en) | 1999-06-10 |
| DE69814690T2 (en) | 2004-01-29 |
| KR20010032668A (en) | 2001-04-25 |
| DE69814690D1 (en) | 2003-06-18 |
| CN1161334C (en) | 2004-08-11 |
| PT1048651E (en) | 2003-09-30 |
| HK1034073A1 (en) | 2001-10-12 |
| DK1048651T3 (en) | 2003-07-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2582668B1 (en) | Carboline carboxamide compounds useful as kinase inhibitors | |
| EP2145887B1 (en) | Substituted 2,3,4,5-tetrahydro-1h-pyrido[4,3-b]indoles, methods for the production and use thereof | |
| ES2669581T3 (en) | Pyrazolo [1,5-a] pyrimidine compounds as TRK kinase inhibitors | |
| CN102482221B (en) | Bicyclic and tricyclic compounds as kat ii inhibitors | |
| WO2003000657A1 (en) | Diamine derivatives | |
| CN101622241B (en) | Benzimidazole compound and pharmaceutical use thereof | |
| KR20020093974A (en) | Azabicyclic Carbamates and Their Use as Alpha-7 Nicotinic Acetylcholine Receptor Agonists | |
| CN1469878A (en) | Aza-and polyaza-naphthalenyl carboxamides useful as HIV integrase inhibitors | |
| CN1439001A (en) | Tetrahydropyridino or piperidino hetlrocyclic derivatives | |
| JP2008523126A (en) | Bicyclic and tricyclic substituted phenylmethanones as glycine transporter I (GLYT-1) inhibitors for the treatment of Alzheimer's disease | |
| TW201920169A (en) | Tetrahydro-imidazo quinoline compounds as CBP/p300 inhibitors | |
| CN1900075A (en) | Tetrahydro-proto-berberine compounds, their preparing method, composition and use | |
| CN1910190A (en) | Thienopyrimidine and thienopyridine derivatives substituted with cyclic amino group | |
| CN1771234A (en) | Process for preparing pyrrolotriazine kinase inhibitors | |
| CN87100298A (en) | Improving one's methods of preparation quinoline-3-carboxylic acid antiseptic-germicide | |
| CN1458933A (en) | Thienopyrimidine compounds and their salts and process for preparation of both | |
| CN1097459C (en) | Diazepino-indoles as phosphodiesterase IV inhibitors | |
| CN1161334C (en) | Nitrogen-containing tetracyclic compounds | |
| JP2546770B2 (en) | Perhydro-1H-pyrido [1,2-a] pyrazine, a psycholeptic agent | |
| CN1143644A (en) | N-[(1,4-diazadicyclo [2,2,2] oct -2-yl methyl] benzoic amide derivatives, its preparing process and medicinal use | |
| JP2003183286A (en) | Diamine derivative | |
| CN1146768A (en) | Process for producing epoxide | |
| CN1910185A (en) | Pyrrolopyrimidine and pyrrolotriazine derivatives as CRF receptor antagon | |
| CN1341095A (en) | Amide compounds for potentiation of cholinergic activity | |
| CN1118456C (en) | 1,2-dihydro-2-oxoquinoline derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1034073 Country of ref document: HK |
|
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |